PROJECT SUMMARY ? This application addresses critical needs and deficiencies in prostate cancer (PCa) patient management. The five year survival rates for localized primary PCa are excellent, but sadly fall to below 1 in 3 for those with metastatic disease. The deluge of academic and clinical efforts to harness targeted agents for imaging of Prostate Specific Membrane Antigen (PSMA), widely overexpressed on prostate cancer tissues, for improved detection represents a sea change in how malignant disease will be monitored. Advancing close behind is a systematic evaluation of therapeutic variants of these agents that deliver an ionizing radiation dose to PSMA- expressing sites of disease. There is considerable interest in alpha particle (?-particle) emitting radionuclides for this targeted radiotherapy as the high linear energy transfer imparts 5-8 MeV in a dense track that is only several cell diameters in length. Unfortunately, widespread background-organ expression of PSMA results in untoward side-effects of absorbed dose to normal tissues. Off-target toxicity places limitations on the activity dose which may be administered; the patient population eligible for the treatment; the requirements for involved long term care of comorbidities; and ultimately the overall impact this treatment will have in the clinic. Here, we propose a strategy that enables organ specific reduction in absorbed dose without affecting tumor targeted uptake. We focus on the salivary glands and kidneys; radiosensitive organs that demonstrate intense PSMA-ligand targeting in pre- and clinical imaging and treatment studies. We have developed and acquired significant insight into a novel prodrug, Tris-POC-2-PMPA that is preferentially deliverd to the kidneys and salivary, and selectively cleaved in these organs, to release the high affinity PSMA inhibitor, 2-PMPA. Our Preliminary Data demonstrate the potential to ensure that tumor specific ablation without toxicity can be achieved while sparing kidney and salivary tissue. Taking advantage of a hybrid imaging and therapy approach, we will define the optimal treatment course required for tumor control, without normal organ toxicity, in multiple small animal xenograft and in an advanced genetically engineered model that most closely recapitulates human disease. This application is being undertaken by a multidisciplinary team composed of experts in radiochemistry, medical physics, pathology, drug development and clinical molecular imaging. This group of investigators and the strength of our data addressing key issues in alpha particle emitting radiopharmaceutical development demonstrate that this application has the potential to realize the transformative capabilities of molecularly targeted radiotherapy for cancer patients.